Pharm E4- Toxicology

Which is a constellation of specific signs and symptoms that indicate exposure to a specific toxin?

Toxidrome

What is a toxic substance produced from natural sources (ex- botox, snake venom)?

Toxin

What is the MOA of cholinergic poisoning?

Inhibition of acetylcholinesterase → too much Ach → excess nicotinic & muscarinic activation

*initially reversible but can become a permanent covalent bond → aging; takes time to produce new esterase

What are examples of organophosphates (OPs)?

Parathion, malathion, chlorpyrifos

*insectisides, really toxic

What are examples of carbamates?

Physostigmine, neostigmine, carbofuran, carbaryl

*plant sources

What are examples of nerve gasses?

Sarin, soman, tabun

*chemical / terrorist attacks

What agents cause cholinergic poisoning?

Organophosphates, carbamates, nicotine, pilocarpine, nerve gassess

Which agents that cause cholinergic poisoning cause irreversible aging?

Organophosphates (slower) & nerve gases (faster)

Which agents that cause cholinergic poisoning are reversible?

Carbamates

What is the mnemonic for muscarinic toxicity symptoms?

Defecation

Urination

Miosis

Bradycardia

Bronchorrhea

Bronchospasm

Emesis

Lacrimation

Salivation

*wet!!

What is the mnemonic for nicotinic effects?

*present first but overshadowed by muscarinic

Mydriasis

Tachycardia

Weakness

Hypertension

Fasciculations → weakness, diaphragmatic failure

What CNS effects can be seen with cholinergic toxicity?

HA, confusion, slurred speech, ataxia, delirium, psychosis, seizure

Which agent responsible for cholinergic poisoning is more lipophilic, containing hydrocarbon bases which is more likely to injure lung tissue?

Organophosphates

What is the treatment for cholinergic poisoning?

ABC’s, decontamination w/ lipid soluble compounds (mild detergent/bleach)

Antidotes: Atropine, pralidoxime

Seizures: BZDs, barbiturates, propofol

How does atropine work to treat cholinergic poisoning?

Dry pulmonary secretions → goal is clear lung exam

*just a bandaid, does not fix problem

What is the true antidote for cholinergic poisoning?

Pralidoxime → prevents covalent bond/aging, treat x 12-24 hrs post last dose of atropine

*fixes the problem

What agents cause anticholinergic toxicity?

Plants (belladonna alkaloids- scopolamine, jimson weed, angel’s trumpet), 1st gen antihistamines (cough and cold preparations), antidepressants (TCAs), 1st gen antipsychotics

What is the MOA of antimuscarinic poisoning?

Competitive blockade at postsynaptic muscarinic receptors

What is the mnemonic for anticholinergic poisoning?

Red as a beet: cutaneous vasodilation→ flushing

Mad as a hatter: CNS depression to severe psychosis / hyperexcitation, seizures at high doses

Blind as a bat: mydriasis, dec accommodation to light, blurry vision

Hot as a hare: hyperthermia

Dry as a bone: dec secretions→ dry mouth, urinary retention

Bowel & bladder lose their tone: dec motility & bowel sounds, delayed absorption

Heart runs alone: tachycardia, hypotension

Why should you listen to bowel sounds in a patient presenting with anticholinergic toxicity?

To determine if the GI tract starts back up because there may be substances in the stomach that are still not absorbed yet, so they could start to get sick again

What is the treatment for anticholinergic poisoning?

Mainstay: supportive; ABC’s, GI decontamination (charcoal)

Seizures: BZDs

Tachy: fluids & BZDs

Antidote: physostigmine (rarely used)

What drug?

• acetylcholinesterase inhibitor

  • carbamate - reversible inhibition (no aging)

• antidote for anticholinergic toxicity → indicated for refractory psychosis / seizures

  • stimulates muscarinic, nicotinic, & somatic receptors, affecting multiple areas

Physostigmine

What are CIs to physostigmine?

Asthma, COPD, TCA ingestions, & can cause cholinergic crisis if dose too high

*avoid unless refractory

Why should rapid administration of physostigmine be avoided?

Can cause cholinergic symptoms → bradycardia, seizures, hypersalivation

What are 3 classifications of agents that cause sympathomimetic toxicity?

Alpha agonists: PPA, phenylephrine, imadazolines

Beta agonists: albuterol, clenbuterol, theophylline/ caffeine

Mixed: epi, pseudoephedrine, ephedrine, amphetamines, PCP, MAOI, LSD, cocaine, acid

Which agents that cause sympathomimetic toxicity are direct agonists at sympathomimetic receptors?

PPA, phenylephrine, epinephrine

Which agents that cause sympathomimetic toxicity do so by increasing release of endogenous catecholamines?

Cocaine, amphetamines

Which agents that cause sympathomimetic toxicity block reuptake/ inhibit metabolism?

MAOIs, antidepressants

What symptoms are seen with alpha stimulation?

Mydriasis, arterial vasoconstriction, diaphoresis, platelet aggregation (clots, strokes, MI) → hypertension w/ normal or decreased heart rate

What symptoms are seen with Beta 1 stimulation?

Increased inotropy & chronotropy → tachycardia +/- BP effects

What symptoms are seen with beta 2 stimulation?

Smooth muscle relaxation in lungs & arteries, arterial vasodilation hypokalemia (ex: clenbuterol - shifts too much K inside cell) → tachycardia with hypotension

What agent that causes sympathomimetic toxicity is a mixed agonist that causes alpha and beta effects?

Theophylline

Anticholinergic or sympathomimetic toxicity?

• disorientation

• agitation

• mydriasis

• hyperthermia

• moist mucous membranes & skin

• increased intestinal motility

Sympathomimetic

Anticholinergic or sympathomimetic toxicity?

• disorientation

• agitation

• mydriasis

• hyperthermia

• urinary retention

• dry mucous membranes & skin

• decreased intestinal motility

Anticholinergic

What is the treatment for sympathomimetic toxicity?

Supportive: ABCs, GI decontamination (depends on route), place in calm/ cool environment, evaporative cooling & icepacks

BZDs for HTN, tachy, agitation, seizures

Short acting CV agents: emolol + nitroprusside

Why should a BB never be given alone to a sympathomimetic overdose such as cocaine?

Unopposed alpha stimulation / squeeze which inc BP → give with antihypertensive (ex- esmolol + nitroprusside)

What term refers to naturally occurring alkaloids (ex- morphine & codeine derived from papaver somniferum)?

Opiate

What term refers to all non-natural substances w/ opiate like effects (ex- fentanyl, tramadol, buprenorphine)?

Opioid

What is the order from fastest onset to slowest onset for opioid intake routes?

Inhaled > IV > oral

Which has a shorter DOA, morphine or methadone?

Morphine

The following clinical presentation is associated with what toxicity?

• CNS: analgesia, sedation, euphoria, dysphoria

• Miosis

• Pulm edema, respiratory depression (turns off brainstems response to CO2 → stop breathing)

• Bradycardia, hypotension

• Decreased bowel motility, N, V

• Hypothermia

Opioids

What 2 agents slow down the GI tract?

Opioids & anticholinergics

What agents that cause opioid poisoning inhibit serotonin uptake?

Meperidine, dextromethorphan, tramadol

What agents that cause opioid toxicity may induce seizures?

Propoxyphene, meperidine, tramadol

What agent is a partial opioid agonist that may cause an atypical presentation in toxicity?

Buprenorphine

Which agents are detected on a UDS?

THC, cocaine, amphetamines, PCP, BZD, barbiturates

Opioids: heroin, morphine, hydrocodone, codeine

*opioids not detected: low concentrations of oxycodone, fentanyl, tramadol

What is the treatment for opioid toxicity?

ABCs, GI decontamination, naloxone

What is the best way to determine if opioids are the reason for a patient presenting with a toxidrome?

Trial naloxone & see if they respond

*if you get up to 10 mg w/ no response → different cause

How should naloxone be given?

Too much can cause withdrawal so give just enough to get them breathing to blow off CO2 / arouse to voice (sweet spot → yawning)

DOA 20-90 min, call 911 after given or give continuous drip

What agents are sedatives / hypnotics?

BZDs: alprazolam, midazolam, lorazepam

Barbiturates: butalbital, phenobarbital

Muscle relaxants: Cyclobenzaprine, carisoprodol, baclofen

Misc: ethanol, chloral hydrate, GHB

What is the MOA of sedative / hypnotive toxicity?

Activate GABA receptor → increase Cl influx → inhibit APs → depresses CNS function

The following clinical presentation is associated with which toxidrome?

• CNS: depressed mentation, nystagmus, ataxia

• Respiratory depression

  • depends on agent; BZDs alone rarely cause

• Hypotension (barbiturates)

• Decreased GI motility

• Some have anticholinergic SEs (carisoprodol, cyclobenzaprine)

Sedatives / hypnotics

What is the treatment for sedative / hypnotic overdose?

ABCs

Hypotension: fluids & pressers (NE preferred for alpha squeeze, not as much on heart)

What is the antidote for an accidental exposure to BZDs?

*do NOT use in chronic BZD use → withdrawal seizures, deadly

Flumazenil

What should be given in addition for treatment of sedative toxicity if due to phenobarbital?

Sodium bicarbonate for urinary alkalinization (spills in urine to metabolize faster) or multi-dose charcoal

What differentiates opiate withdrawal from sedative / hypnotic withdrawal?

*both have anxiety, agitation, irritability, GI hyperactivity, tachycardia, HTN

Withdrawal seizures occur with sedatives, not opiates

Which agents cause bradycardia?

Cholinergics, clonidine (dec NE release), non-DHP CCBs, BBs, digoxin (+ xanthopsia)

What agents cause tachycardia?

Sympathomimetics, anticholinergics, theophylline, iron, salicylates, antihistamines, neuroleptics

Which agents cause hypotension?

Clonidine, CCBs, TCAs, sedatives / hypnotics, iron, salicylates, digoxin, significant acidosis (NE cant bind as well)

What agents cause HTN?

Sympathomimetics, anticholinergics, nicotine, caffeine, thyroid supplements (levothyroxine abused for weight loss)

What agents cause hypothermia?

Opioids, hypoglycemics, carbon monoxide (generators / cars in garage, house fires), sedatives / hypnotics (unconscious, not physically active for long periods)

What agents cause hyperthermia?

Anticholinergics, sympathomimetics, salicylates, phenothiazines, antidepressants, thyroid preparations

What agents cause bradypnea?

Clonidine, opioids, sedatives/ hypnotics

What agents cause tachypnea?

Salicylates (early sign of poisoning), cyanide (house fires burning synthetic fibers, apples / peach pits), irritant gasses (chemical cleaners, bleach + cat urine / ammonia → chlorine gas)

What agents cause miosis?

Cholinergics, clonidine, opiates, sedatives/ hypnotics

What agents cause mydriasis?

Anticholinergics, antidepressants, sympathomimetics, phenothiazines

What agents cause diaphoresis?

Sympathomimemtics, OPs, salicylates

What agents cause bullae (pressure ulcer / blister filled with fluid from being down for long period)?

Barbiturates, carbon monoxide

What agents cause dry mucous membranes?

Anticholinergics

What agents cause flushed skin?

Anticholinergics, carbon monoxide, cyanide, boric acid (roach tablets, certain cleansers)

What smell would indicate cyanide?

Bitter almonds

What smell would indicate water hemlock?

Carrots

What smell would indicate arsenic or pesticides?

Garlic

What smell would indicate camphor?

Mothballs

What smell would indicate chloral hydrate?

Pears

What smell would indicate methyl salicylate?

Wintergreen

What smell would indicate hydrogen sulfide (or anything with sulfur)?

Rotten eggs

What agents cause a wide anion gap (> 16)?

Methanol- windshield wiper fluid

Uremia - check BMP

DKA

Paraldehyde

Isoniazid, iron

Lactic acidosis

Ethylene glycol- radiator fluid, sweet

Salicylates

Less common: cyanide, CO, alcoholic ketoacidosis, toluene (paint thinner)

What agents are radiopaque on imaging?

Chloral hydrate, heavy metals / lead, iron, phenothiazines, enteric coated product, salts (potassium)

How should areas exposed to fat soluble or oil based products be flushed?

Water with soap / mild detergent, diluted bleach solns

How do you perform ocular decontamination?

Remove contacts & use Morgan lenses connected to IV line for continuous saline flushing (or use nasal cannula if unavailable), irrigate atleast 15-30 min

*end goal → normal lacrimal pH 7.2

What decontamination agent that stimulates chemoreceptor trigger zone to initiate emesis was removed from the market d/t being ineffective, aspiration risk & causing cardiomypothay in bulimic patients?

Ipecac

How is gastric lavage performed?

Used for life threatening ingestion w/in 1 hr → left lateral decubitus position, tap water or saline instilled into stomach via NG tube & removed by gravity / suction

What are CIs to gastric lavage?

Aspiration risk, FB ingestion, toxin that is bigger than lovage tube hole, corrosive or hydrocarbon ingestions (burns)

complications → aspiration, esophageal perforation d/t corrosive ingestion (draino)

What is the time frame for activated charcoal?

Within 1 hour of ingestion

*2 hours if opioids or anticholinergics

What agents does activated charcoal (AC) NOT bind to?

Alcohol, heavy metals, iron, lithium, hydrocarbons (lighter fluid, gas from car)

What are CIs to AC?

Aspiration (make sure pt is upright & lucid), intestinal obstruction, corrosive ingestion

How is whole bowel irrigation performed?

Flush 500ml - 2L/hr of polyethylene glycol to force through tract more quickly (given through NG tube d/t bad taste) → end goal is clear recall effluent

*must confirm placement of tube in stomach w/ stethoscope (blow air & hear bubbles) to prevent aspiration

What agents would whole bowel decontamination be good for?

Heavy metals, concretions / bezoars, body packers (smuggling drugs, more well wrapped & less likely to come up in tract), body stuffers (dealing on streets & swallows drugs to hide from cops, not well wrapped, more likely to be exposed)

What toxic byproduct of APAP toxicity forms covalent bonds that causes cell death and free radical production (usually neutralized by glutathione / GSH but dangerous when stores run out)?

NAPQI

What patients are predisposed to APAP toxicity?

Inc frequency of dosing for chronic pain, prolonged use of excessive doses, chronic alcoholics w/ liver impairment, induction of CYP2E1, decrease GSH (less substrate to process APAP)

Which stage of APAP toxicity?

• may be asx

• no hepatic injury

• N/V, malaise, pallor, diaphoresis

• dec LOC & metabolic acidosis if massive ingestion

Stage 1 - 0-24 hrs

Which stage of APAP toxicity?

• Transaminase elevations

  • Inc AST/ALT w/ actual damage to cells, but doesn’t tell you how well liver is actually functioning

• Inc PT/INR, bilirubin, lactate

  • PT/INR better indication of liver function - not producing clotting factors (bad sign)

Stage 2 - 24-36 hrs

Which stage of APAP toxicity?

• Further elevation of transaminases

  • if PT/INR still inc but ALT/AST dec → no enzymes left

• jaundice, hepatic encephalopathy, renal failure

• metabolic acidosis

• death from hepatic failure: 3-5 days

Stage 3 - 72-96 hrs

Which stage of APAP toxicity?

• recovery phase

• weeks-months for complete resolution

  • rare but some may need liver transplant

Stage 4

What are the toxic levels of APAP?

Adults: 7.5 g

Kids: 150-200 mg/kg

Know the APAP nomogram

**Test Q

above line → treat; below line → do nothing

wait until 4 hrs after ingestion to draw levels

single one time ingestion only, not for chronic use**

What is the treatment for APAP toxicity?

ABCs (co-ingestion), AC if appropriate (w/in 1 hr, conscious, tolerate PO), tx hypoglycemia, Vit K or blood products if coagulopathy, transplant (rare)

Antidote: n-acetylcysteine

What drug?

• APAP antidote → replaces substrates in all 3 pathways that handles APAP

  • Substrates & precursor for GSH, donates sulfhydryl groups

• smells like rotten eggs (sulfur)

• IV: Acetadote- expensive; use if suicidal or noncompliant

• PO: mucomyst- cheaper; mix w/ sprite & use straw/ cover to mask bad smell/ taste

• stop when LFTs recovering, APAP is undetected, & PT/INR is normal

N-acteylcysteine

What is the timeframe from ingestion that N-acetylcysteine is 100% effective (pt won’t die)?

*still effective after by scavenging free radicals & limiting damage

8 hours